The present invention relates to a gastroresistant vector intended to be administered orally and containing at least one therapeutically and/or prophylactically active substance, to the use thereof and to the process for producing same.
Oral administration has many advantages for delivering medicaments and also vaccines. The bioavailability of an orally administered active ingredient is greatly reduced if the compound is degraded during its passage through the stomach regions that are generally rich in enzymes and are characterized by a very acidic pH. The purpose of the digestion mechanism is in fact to lyse a maximum number of chemical bonds so as to make macromolecules absorbable, by breaking them down into forms of smaller molecules. For large complex molecules, which medicinal active ingredients or vaccines generally are (in particular those based on proteins), this results in a loss of efficacy.
Nevertheless, for administering oral treatments, two major strategies exist for getting over the gastric barrier:                administering large amounts of active ingredient: thus, even if a high proportion is degraded, an active part thereof will remain;        carrying the active ingredient in an excipient that will protect it against degradation in the acidic stomach region and will release it in the effective region at neutral pH.        
This second technique is referred to as placing in gastroresistant form. It is widely used in the form of gel capsules (which are filled with the active ingredient) or of tablets film-coated with at least one polymer film which is insoluble at acidic pH and soluble at neutral pH.
The filling of gel capsules and the film-coating of tablets are very complex, expensive industrial processes and do not make it possible to go down to administration units of very small size (the limiting size being that of the gel capsules and of the tablets). For film-coating, which can be envisioned for microgranules a few millimeters in diameter, this requires very specific, expensive equipment and processes for depositing gastroresistant films, requiring hot ventilation to evaporate off the solvent used to deposit the film on the moving support granules. This process is thus not usable for heat-sensitive active ingredients (such as, for example, vaccine antigens) and active ingredients of which the dust is toxic. Furthermore, it is virtually impossible, because of the filling and film-coating constraints, to work aseptically to produce sterile pharmaceutical products.
Liquid forms encapsulating hydrophilic active ingredients in oily matrices (for example water-in-oil emulsions) are used to “protect” and gradually release active ingredients and antigens by the injectable route (for example, the emulsion for oral administration of example 2 of patent EP 0 073 006), but do not withstand passage through the digestive system and are dissociated and destructured when they pass through the stomach.
Thickening polymer matrices ensuring the formation of a very slowly disintegrating tablet provide, through this gradual release, a gastroresistant effect, as described in patent application WO 2001/078688. If the matrix dissolution kinetics are calculated over the stomach/intestine transit time, the end fraction, which is released in the intestine, has crossed the stomach barrier, whereas the initial fraction, dissolved in the stomach, has been digested. The term delayed-effect matrix is used rather than true gastroresistance. In this case, the matrix must be large in size (for example, a tablet to be injected orally) to be adjusted according to the transit kinetics, the transit kinetics being variable according to recipient species, food bolus, age, type of digestion (fish, ruminants, etc.). The performance levels of matrices of this type are variable.
Polymer macromolecules, in order to be used in oral formulations, must be soluble at neutral pH: this is because the release of the active ingredients is thus ensured. The largest molecules (high-molecular-weight polymers) give the best protection during passage through the acidic regions. However, these polymers all have the drawback of causing the viscosity of aqueous solutions to increase, converting them into gel or semi-solids that cannot be poured, are difficult to quantitatively determine and difficult to absorb.
Gastroresistant polymers cannot be used directly at a high content in aqueous solutions since the high viscosity that they develop prevents flow. Moreover, it is known that the gels of these polymers, at acidic pH, form a precipitate of said polymer.
These precipitates, put back to a neutral pH, make it possible to release the molecules trapped during the precipitation of the polymers.